Raynes Yevgeniy, Weinreich Daniel M
Department of Ecology and Evolutionary Biology, Center for Computational Molecular Biology Brown University Providence Rhode Island.
Evol Appl. 2018 Oct 11;12(2):301-313. doi: 10.1111/eva.12717. eCollection 2019 Feb.
Most solid cancers are characterized by chromosomal instability (CIN)-an elevated rate of large-scale chromosomal aberrations and ploidy changes. Chromosomal instability may arise through mutations in a range of genomic integrity loci and is commonly associated with fast disease progression, poor prognosis, and multidrug resistance. However, the evolutionary forces promoting CIN-inducing alleles (hereafter, CIN mutators) during carcinogenesis remain poorly understood. Here, we develop a stochastic, individual-based model of indirect selection experienced by CIN mutators via genomic associations with fitness-affecting mutations. Because mutations associated with CIN affect large swaths of the genome and have the potential to simultaneously comprise many individual loci, we show that indirect selection on CIN mutators is critically influenced by genome organization. In particular, we find strong support for a key role played by the spatial clustering of loci with either beneficial or deleterious mutational effects. Genomic clustering of selected loci allows CIN mutators to generate favorable chromosomal changes that facilitate their rapid expansion within a neoplasm and, in turn, accelerate carcinogenesis. We then examine the distribution of oncogenic and tumor-suppressing loci in the human genome and find both to be potentially more clustered along the chromosome than expected, leading us to speculate that human genome may be susceptible to CIN hitchhiking. More quantitative data on fitness effects of individual mutations will be necessary, though, to assess the true levels of clustering in the human genome and the effectiveness of indirect selection for CIN. Finally, we use our model to examine how therapeutic strategies that increase the deleterious burden of genetically unstable cells by raising either the rate of CIN or the cost of deleterious mutations affect CIN evolution. We find that both can inhibit CIN hitchhiking and delay carcinogenesis in some circumstances, yet, in line with earlier work, we find the latter to be considerably more effective.
大多数实体癌的特征是染色体不稳定（CIN）——大规模染色体畸变和倍性变化的发生率升高。染色体不稳定可能通过一系列基因组完整性位点的突变产生，通常与疾病快速进展、预后不良和多药耐药性相关。然而，在致癌过程中促进CIN诱导等位基因（以下简称CIN突变体）的进化力量仍知之甚少。在这里，我们开发了一个基于个体的随机模型，用于研究CIN突变体通过与影响适应性的突变的基因组关联所经历的间接选择。由于与CIN相关的突变会影响大片基因组，并且有可能同时包含许多单个位点，我们表明对CIN突变体的间接选择受到基因组组织的关键影响。特别是，我们发现具有有益或有害突变效应的位点的空间聚类发挥了关键作用，这一观点得到了有力支持。所选位点的基因组聚类使CIN突变体能够产生有利的染色体变化，从而促进它们在肿瘤内的快速扩增，进而加速致癌过程。然后，我们研究了人类基因组中致癌基因和抑癌基因位点的分布，发现两者在染色体上的聚类程度可能比预期的更高，这使我们推测人类基因组可能容易受到CIN搭便车效应的影响。不过，要评估人类基因组中聚类的真实水平以及对CIN间接选择的有效性，还需要更多关于单个突变适应性效应的定量数据。最后，我们使用我们的模型来研究通过提高CIN发生率或有害突变成本来增加基因不稳定细胞有害负担的治疗策略如何影响CIN进化。我们发现，在某些情况下，这两种策略都可以抑制CIN搭便车效应并延缓致癌过程，但与早期工作一致，我们发现后者的效果要显著得多。
